The biology of mycobacterium tuberculosis infection

Abstract

Tuberculosis (TB) still poses a major threat to mankind and during the last thirty years we have seen a recrudescence of the disease even in countries where TB was thought to be conquered. It is common opinion that more effective control tools such as new diagnostics, a new vaccine and new drugs are urgently needed to control the global pandemic, though the so far insufficient understanding of the Mycobacterium tuberculosis (Mtb) mechanism of pathogenesis is a major obstacle for the development of these control tools. In this review, we will summarize the recent advancement in the understanding of Mtb biology and on the pathogenesis of Mtb infection with emphasis on latent infection, with the change in paradigm of the last few years where the dichotomy between latent and active disease has been reconsidered in favor of a dynamic equilibrium between the host and the bacilli, encompassing a continuous spectrum of conditions that has been named TB spectrum. Implications for the diagnosis and control of disease in certain population will also be discussed.

Figure 1. Protein Secretion systems

Five different secretion system have been described in Mtb (titled Type VII Secretion System -T7SS), encoded by gene clusters and called ESX1 to ESX5. ESX1 and ESX5 secrete different proteins involved in the virulence of Mtb: ESX1 secretes antigens that interfere with the integrity of the phagosomal membrane, leading to phagosomal rupture and bacterial emission into the cytosol. ESX5 is present only in slow growing mycobacteria (such as Mtb and M. marinum) and it is thought to be involved in the secretion of proteins (PPE and PE-PGRS) with immunomodulatory properties. ESX3 is involved in Zinc and Iron uptake and homeostasis and as such is essential for growth. The role of ESX2 and ESX4 remain still unknown.

Figure 2. TB pathogenesis

Tubercle bacilli are inhaled in aerosol droplets, enter into the lungs and, when the host innate immune defenses fail to eliminate the bacteria, Mtb start multiplying inside alveolar macrophages and then spreads to other tissues and organs through the bloodstream and lymphatics. Once the cell-mediated immune response kicks in, bacterial replication is usually controlled and in 90–95% of cases non overt signs or symptoms of disease ensue (Latent TB). During latent infection a dynamic equilibrium between the bacilli and host immune responses is established and any event that weakens cell mediated immunity may lead to active bacterial replication, tissue damage and disease occurs (active TB).